Activin receptor-like kinase 7 induces apoptosis of pancreatic beta cells and beta cell lines

Diabetologia. 2006 Mar;49(3):506-18. doi: 10.1007/s00125-005-0095-1. Epub 2006 Jan 27.


Aims/hypothesis: Activin receptor-like kinase 7 (ALK7), a member of the type I receptor serine/threonine kinases of the TGF-beta superfamily, was recently reported to regulate cell proliferation and apoptosis. We hypothesised that ALK7 may play a role in modulating pancreatic beta cell proliferation and/or apoptosis.

Methods: We detected ALK7 expression in beta cells using RT-PCR, immunostaining and western blotting. Constitutively active, dominant negative or wild-type ALK7 was introduced into beta cells using adenoviral delivery. Proliferation was assessed using (3)H-thymidine incorporation and apoptosis was quantified using terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling detection, DNA degradation analysis and caspase-3 assays.

Results: Induction of constitutively active ALK7 in beta cells resulted in growth inhibition and enhanced apoptosis; no effect was seen with INS-1 cells expressing wild-type or dominant negative ALK7. Elevated glucose concentrations and fatty acid (palmitate) markedly increased expression levels of ALK7 transcripts and proteins in INS-1 and rat islets and increased beta cell apoptosis. Activation of ALK7 increased Smad2 phosphorylation, reduced protein kinase B (Akt) kinase activity and was associated with increased levels of the bioactive forms of caspase-3, whereas co-expression of constitutively active ALK7 with dominant negative Smad2 or constitutively active Akt significantly diminished ALK7-induced growth inhibition and apoptosis in INS-1 cells. Although overexpression of constitutively active Akt significantly reduced ALK7-induced growth inhibition and ALK7-enhanced beta cell apoptosis, ALK7-stimulated Smad2 phosphorylation was not affected.

Conclusions/interpretation: These results suggest that the pancreatic beta cell apoptosis induced by ALK7 activation occurs via the activation of two distinct downstream pathways: the suppression of Akt activation and the activation of the Smad2-caspase-3 cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism*
  • Animals
  • Apoptosis* / genetics
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Fatty Acids / pharmacology
  • Gene Expression Regulation
  • Glucose / pharmacology
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / enzymology*
  • Male
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Smad2 Protein / metabolism


  • Fatty Acids
  • Smad2 Protein
  • Smad2 protein, rat
  • Proto-Oncogene Proteins c-akt
  • Activin Receptors, Type I
  • Acvr1c protein, rat
  • Caspase 3
  • Glucose